Decahydroisoquinoline derivatives



3,015,661 DECAHYDROISOQUINOLINE DERIVA Vlasios Georgian, 2626 Princeton,Evanston, 1]]. No Drawing. Filed Sept. 4, 1958, Ser. No. 758,926 8Claims. (Cl. 260-287) This invention relates to novel heterocyclics,more particularly to certain hydrocarbazolenines and a process for theirproduction and to their use in the production of alkaloids andalkaloid-like compounds.

It is an object of this invention to provide novel hydrocarbazolenines.Another object is the provision of certain hydrocarbazolenines useful inthe production of intermediates convertible to natural alkaloids. Stillanother object is the provision of hydrocarbazolenines useful in theproduction of dihydrothebainone and isostrychnine-I. A further object isa provision of a process for the production of hydrocarbazolenines,especially from polycyclic ketones. Other objects will be apparent tothose skilled in the art to which this invention pertains.

The novel hydrocarbazolenines of the invention are prepared by reactinga Z-hydrdarylhydrazine with a fused hydroaromatic ketone having avicinal bridgehead-hydrogen atom and cyclizing with an acidic cyclizingagent the arylhydrazone thus formed.

The term Z-hydroarylhydrazine is intended to refer to an aromatichydrazine having a hydrogen in the 2- position with respect to anunsubstituted hydrazino radical, --NHNH The Z-hydroarylhydrazines of theinvention can, for the most part, be represented by the formula:

NEE-NH: I

wherein R is zero to four indifferent radicals. Since by definition the2-position is occupied by hydrogen, the R substituent or substituentscan occupy any or all of the 3-, 4-, 5-, and 6-positions. By indifferentradicals is meant radicals which do not interfere with the reaction ofthe 2-hydroarylhydrazine with a ketone to form a hydrazone. For the mostpart R can be represented as from zero to four radicals selected fromthe class consisting of lower-hydrocarbon radicals, inclusive oflowerhydrocarbon radicals fused with the phenyl group to form a bicyclicstructure, hydroxy, ether radicals containing up to eight carbon atoms,cyano, carboxy, esterified carboxy radicals containing up to eightcarbon atoms, amino, acylamido in which acyl is the acyl radical of acarboxylic acid containing up to eight carbon atoms, carboxymethoxy(-OCH COOH), sulfo, nitro, and halogen. It is to be understood that anether radical is one having ether attachment to the ring as in alkoxy,aralkoxy, and alkylmercapto.

The term fused hydroaromatic ketone having a vicinal bridgehead-hydrogenatom is used to designate a compound having at least two fused rings,i.e., having two carbon atoms common to both rings, one of which is asix-membered carbocyclic ring having an oxo substituent attached to acarbon atom adjacent to a bridgeheadcarbon bearing a hydrogen atomwhereby the bridgeheadhydrogen is vicinal to the keto group. Fusedhydroaromatic ketones of this type can, for the most part, berepresented by the following formula:

Kill

3,015,661 Patented Jan. 2, 1962 three indifferent radicals, and R" is avalence satisfied by hydrogen, a lower-alkyl radical, a lower-arylradical, or an olefinic linkage comprised within one of the fused ringstructures. Again by indifferent radicals is meant radicals which do notinterfere with hydrazone formation. For the most part these fusedhydroaromatic ketones can be represented by the above formula when X isan unsubstituted polyvalent radical containing between the valences achain of from three to five atoms. which consists of carbon atoms andfrom zero to one hetero atom; R and R each are from zero to threeradicals selected from the class consisting of lower-hydrocarbonradicals, inclusive of lower'hydrocarbon radicals fused with the nucleusto form a polycyclic structure, hydroxy, ether radicals containing up toeight carbon atoms, esterified carboxy radicals containing up to eightcarbon atoms, carboxyalkyl and esterified carboxyalkyl radicalscontaining up to eight carbon atoms, halogen, nitro, 0x0, cyano,ketalized ketone groups, acyl, ketalized acyl, acyloxy, and acylamidogroups in which acyl is the acyl radical of a carboxylic acid or anaromatic sulfonic acid containing up to eight carbon atoms,lower-aminomethyl radicals, and carboxy and amino radicals wherein saidamino and carboxy groups, when both are present, can be in the form of alactam ring or a reduced lactam ring and wherein said hydroxy andcarboxy groups, when both are present, can be in the form of a lactonering, and R' is as described above. It is to be understood that theC-ring can be either saturated or monoolefinic. The D-ring can besaturated or unsaturated.

Any 2-hydroarylhydrazine as represented above and as exemplified belowcan be reacted with any of the fused hydroaromatic ketones having avicinal bridgeheadhydrogen as represented above and as exemplified belowto give hydrazones which, for the most part, can be represented by theformula:

Rn: D

produce hydrocarbazolenines which, for the most part, can be representedby the formula:

III

wherein R, R, R", R, and X are as set forth above.-

Examples of lower-hydrocarbon radicals according to the above formulaeinclude methyl, ethyl, butyl, hexyl, octyl, and like lower-alkylradicals; lower-alkenyl radicals such as propenyl, isopropenyl, allyland 1,4,5-trimethyl-2- hexenyl and the like; lower-alkylidene radicalssuch as methylene, ethylidene, propylidene and the like; benzyl,phenethyl, phenylpropyl, benzhydryl, naphthyl-rnethyl, cuminyl,ac-tetrahydronaphthyl and like lower-aralkyl radicals; phenyl, tolyl,xylyl, cymyl, cumyl, naphthyl, artetrahydronaphthyl, biphenylyl, andlike lower-aryl radicals; styryl, cinnamyl, phenylallyl, and likelower-aralkenyl radicals; and divalent lower-polymethylene andsubstituted polymethylene hydrocarbon radicals and the correspondingunsaturated divalent radicals which form fused ring structures with thering to which they are attached. Examples of lower-alkyl and lower-arylradicals at valence ILXA M l? TABLE 2 coon NHZNHQ Wolff-manner I NH; 5

diazocization Friedel-Crafts ring closure OCH3 XVI

NH NH Wolff-Kishner hydrolysis 0 of dithioketal can; 0on

XVII XVIII dihydrothebainone TABLE3 0 (H COOR (1) ester 1 hydrolysis (2)acid cat. ring closure U XIII XIX (see Table 2) NH NH doubleWolff-Kishner diazotization XVII (see Table 2) hydrolysisdihydrochebainone TABLE4 NHgNHg N Wolff-Kishner H3 H3 XIX (see Table 3)LIA 1H4 TABLE 4Continued hydrolysis HsH, H+

His

XXII

n O 1 t a z 1 t 0 Z a 1 d dihydrothebainone COOH TABLES so OOH 00H H3 XeXXVI perphthalie acid fie Hiand/or A CH Xe XXVII TABLE ContinuedFriede1-Crafts ring closure OCHs Ac XXIX \l/Wolff-Kishner hydrolysisOCHS H XXXI diazotization 2 OH a xxxrrr CHSI OCHa mrv 0dihydrothebainone R'" are methyl, ethyl, propyl, butyl, hexyl, octyl,phenyl, tolyl, xylyl, and the like. Examples of acyloxy radicals includeacetoxy, propionoxy, butyroxy, valeroxy, capryloxy, and the like.Examples of etherified hydroxy radicals include methoxy, ethoxy,propoxy, butoxy, hexyloxy, octyloxy, phenoxy, benzyloxy, and the like,and the sulfur analogues thereof, e.g., methylmercapto. Examples ofesterified carboxy radicals include carbomethoxy, carbethoxy,carbobutoxy, carbohexyloxy, carboctyloxy, carbobenzyloxy, and the like.Examples of acylamido radicals include acetamido, propionamido,butyramido, valeramido, caprylamido, benzamido, tosylamido, and thelike. Examples of acyl include acetyl, propionyl, butyryl, valeryl,caprylyl, henzoyl, cinnamoyl, tosyl, and the like. Examples of halogenradicals include chlorine, bromine, iodine, and fluorine. Examples ofketalized ketone groups are ethylene glycol ketal, ethylene glycoldithioketal, propylene glycol ketal, propylene glycol dithioketal, andthe like. Examples of ketalized acyl are 2-methyl-l,3- dioxolan-Z-yl,2-.propyl-l,3-dioxolan-2-yl, and the like. Examples of carboxyalkyl andesterified carboxyalkyl radicals are carboxymethyl, carboxyethyl,carboxybutyl, and the methyl, ethyl, and propyl esters thereof. Theradical X is exemplified by 3-, 4-, and 5-atom straight-chain, saturatedand olefinic hydrocarbon radicals, such as:

N -heter0 radicals O-hetero radicals S-hetero radicals and the like. TheN-hetero radicals, X, give ketones which have distinct classcharacteristics in that they are strongly basic nitrogenous compoundswhich form salts and have an N-hydrogen which can be replaced by acyl,alkyl, aryl, and aralkyl groups by conventional methods. Tertiary aminesthus formed are further characterized by their ability to formquaternary ammonium compounds.

The hydrocarbazolenines of the invention are basic nitrogenous compoundsowing to the tertiary amino function at position 9 in the above formula(and are difunctional bases when the D-ring contains a basic nitrogen asa hetero atom) and form salts with acids such as hydrochloric,thiocyanic, sulfuric, phosphoric, picric, acetic, citric, and the like,and alkyl and aralkyl halides such as methyl, ethyl and benzylchlorides, bromides, iodides, and the like. The thiocyanate saltscondense with formaldehyde to form pickling inhibitors according to US.Patents 2,425,320 and 2,606,155.

The hydrocarbazolenines of the present invention have physiologicalactivity, especially analgesic activity. The compounds of the presentinvention are particularly useful as intermediates in the production ofalkaloids such as, for example, morphine, codeine, and strychnine, andalkaloid-like compounds having similar activity. Tables 1, 2, 3, 4, andillustrate processes for the conversion of two types ofhydrocarbazolenines of this invention into alkaloids. Table 1illustrates the conversion of a hydrocarbazolenine (V) according to theinvention to isostrychnine-1(XII), a known strychnine precursor (see TheAlkaloids, by Manske and Holmes, vol. II, page 521, Academic Press,Inc., 1952). Tables 2, 3, 4, and 5 illustrate the conversion of otherhydrocarbazolenines according to the invention to dihydrothebainone(XVIII), a known morphine and codeine precursor [see Gates and Tschudi,J. Am. Chem. Soc. 74, 1109 (1952)].

In carrying out the process of the invention, an arylhydrazone asdescribed above is first prepared by reacting a Z-hydroarylhydrazinewith a fused hydroaromatic ketone having a vicinal bridgehead-hydrogen,or by any other suitable method such as the JappKlingemann reaction. Thecondensation of the hydrazine and the ketone is effected according tothe usual procedures for forming hydrazones. Thu-s the two reagents,advanta geously in stoichiometric proportions, are mixed with or withouta solvent or diluent and the mixture gently heated, advantageously withthe addition of a few drops of glacial acetic acid or like acidcatalyst. The arylhydrazone thus formed is then mixed with a largevolume of acid solution and the mixture heated, advantageously at thereflux temperature, as required to efiect the desired cyclization. Thecyclization, besides the desired hydrocarbazolenine, yields thecorresponding isomeric h'ydrocarbazole (except in the case of blockedketones as explained below) and ammonia. In working up the reactionmixture, advantage can be taken of the basicity of thehydrocarbazolenine in its separation from the non-basic hydrocarbazole.The product hydrccarbazolenine can thus be isolated by removing thesolvent, as by distillation, extracting the residue with an inertsolvent for the free base (the reaction mixture may be neutralized withsodium hydroxide if necessary or desired to liberate the free base),such as ether, e.g., diethyl ether, diisopropyl ether, dibutyl ether,and the like, or a chlorinated hydrocarbon, e.g., chloro form, methylenechloride, chlorobenzene, carbon tetrachloride, and the like, washing theether or other solvent solution with an alkaline solution, e.g., asolution of sodium or potassium hydroxide, as necessary to removeresidual acids and salts, and then extracting the organic solution withaqueous acid, e.g., aqueous hydrochloric or sulfuric acid. Thehydrocarbazolenine is thus taken into the aqueous phase as its salt,e.g., hydrochloride or sulfate, and can be recovered therefrom either asits salt or, after neutralization, as the free base. The hydrocarbazole,if formed in the reaction, remains in the organic phase. Thehydrocarbazolenine can be purified if desired by conventional proceduressuch as vacuum distillation, recrystallization from solvents, or throughsalt formation.

Glacial acetic acid advantageously can be used as the acid solution, asWell as similar alkanoic acids such as propionic acid, butyric acid, andthe like. Aqueous or non-aqueous solutions of acetic acid or other acidssuch as hydrochloric, chloroacetic, dichloroacetic, trichloroacetic, andthe like can also be used, suitable non-aqueous solvents being ethanol,benzene, and the like. Other acids also can be used but sometimes, asfor example with sulfuric acid, the yield of hydrocarbazolenine relativeto hydrocarbazole is impaired.

The proportions of acid solution to arylhydrazone can be varied widelyand the resulting mixture can be either homogeneous or heterogeneous.Advantageously a relatively large volume of acid solution, say fromabout two to about ten -volumes per volume of arylhydrazone, is used.Ordinarily within these proportions homogeneous mixtures or solutionsare obtained throughout the reaction.

The reaction temperature also can be varied widely. Advantageously,however, the temperature is kept between about seventy degreesCentigrade and about degrees centigrade. Ordinarily the atmosphericreflux temperature of the solution is most convenient. or lowertemperatures, say down to about forty degrees centigrade and up to aboutdegrees centigrade, can be used, but at the lower temperatures the timerequired to complete the reaction is prolonged and at the highertemperatures there is danger of decomposition and side reactions. Alsoat the higher temperatures super-atmospheric pressure may be required.Advantageously the reaction is conducted under an inert atmosphere suchas nitrogen, hydrogen, carbon dioxide, and the like.

When the starting ketone contains a primary or secondary basic aminogroup such as would result in the forma tion of a basic hydrocarbazoleas a concomitant product nine will not be affected by the acylation.Alternatively,

the starting ketone can be acylated before it is reacted with theZ-hydroarylhydrazine and the resulting arylhydrazone cyclized to formthe hydrocarbazolenine. If a tertiary amino group is present in thestarting ketone, other methods of separation can be used. Thus thedibasic character of the hydrocarbazolenine, in such case, can beutilized as a basis for separation from the concomitantly producedmonobasic hydrocarbazole.

When the ortho position of the starting ketone is blocked bysubstitution of both hydrogens on the ortho carbon atom, i.e., thecarbon atom ortho to the carbonyl group (not including, of course, thebridgehead-carbon which by definition must carry a hydrogen in order forhydrocarbazolenine formation to be possible), no concomitanthydrocarbazole formation is possible. Advan- Higher tage can be taken ofthis phenomenon to increase the yield of hydrocarbazolenine and toeliminate the need for the separation step. Thus it is possibleaccording to the invention to introduce a protective group, i.e., ablocking group, in the ortho position of such character as may bedesirable in the end product, or of such character as may be removed orconverted to a more desirable group after the hydrocarbazolenine isformed. For example, deca1in-1,2-dione can be converted to itsbis-(phenylhydrazone) which on cyclization can give only thehydrocarbazolenine,1,2,3,4,4a,5,6,7-octahydro-7-phenylhydrazonobenz[d]4aH-isocarbazole. The7-phenylhydrazono group can now be removed by interchange with a moreactive carbonylic compound such as pyruvic acid to give the1,2,3,4,4a,5,6,7-octahydro 7 ketobenz[d]4aH-isocarbazole. A 7-keto groupso introduced can be utilized advantageously in some instances as in thesynthesis shown in Table 4, or if desired the 7-keto group can bereduced to a methylene group by a Wolff-Kishner carbonylic reduction togive 1,2,3,4,4a,5,6,7-octahydrobenz[d]4aH-isocarbazole. Other examplesmay be seen in Tables 3 and 4, supra.

When an arylhydrazone of a starting 2-hydroarylhydrazine having one metasubstituent is cyclized according to the invention, ordinarily twoisomeric hydrocarbazolenines of the invention are produced, theisomerism residing in the position of said substituent in said isomers.

The starting 2-hydroarylhydrazines for use in the process of theinvention are generally well known in the art or can be prepared byconventional methods. Examples of suitable 2-hydroarylhydrazines includephenylhydrazine, p-fiuoro, p-chloro, p-bromo, and p-iodophenylhydrazine,m-, and p-nitrophenylhydrazine, 2,4-dinitrophenylhydrazine, 0-, m-, andp-tolylhydrazine, bromo-oand bromo-p-tolylhydrazines, p-xylylhydrazine,2-naphthylhydrazine (see Richter-Anschiitz, The Chemistry of the CarbonCompounds, Third English Edition, pages 148 and 618);m-carboxyphenylhydrazine [Willstzitter et al., Ann. 418, 127 (1919)];3,5-xylylhydrazine (see C. A. Decennial .Index, vols. 31-40);2,4-xylylhydrazine, phenyl-2,4-xylylhydrazine, 2-nitro panisylhydrazine, o-nitrobenzyl-m-tolylhydrazine, p-(3-methylcyclohexyl)-phenylhydrazine, 3- and -ethyl-2,4-dinitrophenylhydrazine,o-ethylphenylhydrazine, 2,3- and 3,5-dichloro-panisylhydrazine,4-bromo-l-naphthylhydrazine (see C. A. Decennial Index, vols. 21-30);m-anisylhydrazine, p-acetamidophenylhydrazine, p-aminophenylhydrazine,p-secbutylphenylhydrazine, 5 chloro-2,4-dinitrophenylhydrazine,4,5-dimethoxy-3-nitro-o-tolylhydrazine, 2,5- and3,4dirnethoxyphenylhydrazine, oand m-iodophenylhydrazine,4-nitro-Z-carbethoxyphenylhydrazine, p styrylphenylhydrazine (see C. A.Decennial Index, vols. 11-20); 2,4- and 3,4-dichlorophenylhydrazine,l-naphthylhydrazine, 3,5-dibromophenylhydrazine,3,4-dinitrophenylhydrazine, oand p-anisylhydrazine (see C. A. DecennialIndex, vols. 1-10); p-cyanophenylhydrazine [Weissberger and Porter, J.Am. Chem. Soc. 66, 1851 (1944)]; o-carbomethoxyphenyl hydrazine (Millsand Saunders, J. Chem. Soc. 1931, 537); o diphenylhydrazine (Graebe andRateanu, Ann. 279, 267); fiuorenyl-Z- hydrazine (Diels, Ber. 34, 1762);4-hydroxyphenylhydrazine (Altschul, J. Prak. Chem. [2] 57, 202);2-carboxyphenylhydrazine (Fischer, Ber. 13, 680);2-methylmercaptophenylhydrazine (Hodgson, J. Chem. Soc. 1928, 1884);3-hydroxy-4,6-dinitrophenylhydrazine (Bo-rsche, Ber. 54, 676);4-hydrazinophenoxyacetic acid (Howard, Ber. 30, 548);4-(2-rnethylbutyl)phenylhydrazine (Glattfeld, J. Am. Chem. Soc. 49,1046); 4-ethoxypheny1hydrazine (Stoltz, Ber. 25, 1663; D.R.P. 68, 159);S-hydroxy- 4-sulfophenylhydrazine (Beil. XV, 648). See Beilstein, vol.XV, expecially Systems 2068 to 2076, 2078 and 2080.

The fused hydroaromatic ketones which may be employed to produce thestarting hydrazones of the present 16 invention are generally known inthe art or can be prepared by the procedures hereinafter set forth.

Examples of known ketones according to the invention arecis-hydrindan-4-one (Hiickel and Schliiter, Ber. 67, 2107); 1 (04,6dimethylhexyl)-8-methy1hydrindan-4-one (Windaus et al., Ann. 533, 118,127); l-(a-carboxyethyD- 8-methylhydrindan-4-one [Windaus and Thiele,Ann. 521, (1936)];1-(a,6,e-trimethyl-fi-hexenyl)-8-methylhydrindan-4-one [Peak, Nature140, 280 (1937)]; cisand trans-l-deealone; 3-butyl-4-propyl-trans-A 1octalone (Marvel et al., J. Am. Chem. Soc. 61, 2003, 2007);Z-methyl-l-decalone (Cook and Lawrence, J. Chem. Soc. 1937, 817 etseq.); 3-methyl-A -1-octalone and S-methyll-decalone (Barrett et al., J.Chem. Soc. 1935, 1065 et seq.); 2 (N methylanilinomethyl) 1 decalone(Birch and Robinson, J. Chem. Soc. 1944, 501); 2,1'0-diphenyl- 4 hydroxyA' l-hexalone, 2,10-diphenyl-4-hydroxy- A 1 decalone, 2,8,10-triphenyl-4-hydroxy-A -1-hexalone (Allen et al., J. Am. Chem. Soc. 66,1617); 10- methyl-7-acetyl-l-decalone and10-methyl-7-cinnamoyll-decalone (Ruzicka et al., Helv. Chim. Acta 14,1132, 1149 et seq.); A -l-octalone and A -6,7-dimethy1-1-octalone[Bartlett and Woods, J. Am. Chem. Soc. 62, 2933 (1940)];3-methyl-4-propyl-A -1-octalone [Marvel et al., J. Am. Chem. Soc. 61,2003 (1939)]; 7-isopr0pylidene- IO-methyl-I-decalone [Rnzicka et al.,Helv. Chim. Acta 14, 1178 (1931)] 7-isopropyl-10-methyl-l-decalone[Takagi, J. Pharm. Soc. Japan 509, 539 (1924)];7-carboxy-IO-methyl-l-decalone [Ruzicka et al., Helv. Chim. Acta 14,1132 (1931)]; 3-isopropenyl-5,IO-dimethyl-ldecalone (Gillam, J. Chem.Soc. 1941, 60); and 3-isopropyl- 5,10-dimethyl-1-decalone (Bradfield, J.Chem. Soc. 1938, 767).

Examples of more complex known ketones according to the invention are2,4b-dimethyl-7-acetoxy-A -dodecahydrophenanthrenl-one [Kdster andLogemann, Ber. 73, 299 (1940)]; 2,4b-dimethyl-7-hydroxy-Adodecahydrophenanthrenl-one [Sen and Mondal, J. Ind. Chem. Soc. 5, 609(1928)]; cholestan-6-one, cholestan-7-one, 7-ketocho1esten-5,7-ketocholestadien- 3,5,7-ketocholestanyl acetate,6-bromo-7-ketocholestane, 3,12-dihydroxy-7-ketocholanic acid,6-ketocholestanyl acetate, 3-hydroxy-6-ketocholanic acid,Z-carbomethoxy- 2 methyl 7 methoxy1,2,3,4,4a,9,10,10a-octahydrophenanthren-l-one, and other polycyclicketones (see Fieser and Fieser, Natural Products Related toPhenanthrene, third edition, Reinhold Publishing Corp., N.Y.); A-3-(1-cyclohexenyl)-A -1-octalone (Jones, J. Chem. Soc. 1942, 393);1-keto-7-methoxy-1,2,3,4,4a,9, 10,10a-octahydrophenanthrene (Robinsonand Walker, J. Chem. Soc. 1936, 74 7); 9-keto-A-dodecahydrophenanthrene, 2-methoxy-6-keto-A -decahydrochrysene and3-keto-7-methoxy-1,2,3,9,10,1l-hexahydro-1,2-cyclopentenophenanthrene(Rapson and Robinson, J. Chem. Soc. 1935, 1285); 6 keto -A-dodecahydrochrysene (Robinson and Peak, J. Chem. Soc. 1936, 759); A-octalin-l,6-dione and A -5-methyloctalin-1,6-dione (US. 2,674,627).

Other starting ketones which can be prepared by the procedures of theprior art as exemplified by the prior art citations given above are:8-chloro-1-decalone, 8-cyano-l-decalone, 4,7-dimethoxy-l-decalone,4-acetoxy-1- decalone, 4-carboxy-1-decalone, 7-nitro-1-deca1one, 3-nitro-l-decalone, 2-methyl-A -1-octalone, 4-carbethoxymethyl-1-decalone,4-bromo-1-decalone, 4-cyano-1-decalone, 4-acetyl-1-decalone,7-amino-1-decalone, 7-benzamido 1 decalone, 4 (1 ketoethyl) 1 decalone1- ethylene glycol ketal [4-(2-methy1-1,3-dioxolan-2-yl)-1- decalone],decalone-1,3-dione, and 7-carboxymethy1-1- decalone.

The following preparations are illustrative of additional fusedhydroaromatic ketones having a vicinal bridge headhydrogen andprocedures for their preparation, but are not to be construed aslimiting.

1 7 PREPARA'I'ION 1 o II f C O CH:

4-methoxyind0le [Blaikie and Perkin, J. Chem. Soc. 125, 296 1924)], issubjected to acid hydrolysis using hydriodic acid or aluminum chloride,and the resulting 4-hydroxyindole to hydrogenation at a pressure ofabout 2000 pounds per square inch in absolute ethyl alcohol in thepresence of Raney nickel (W-7) plus a trace of SO- dium hydroxide and ata temperature of about 100 to 125 degrees centigrade to form4-hydroxyoctahydroindole. Treatment of this compound with a slightmolecular excess of acetic anhydride in absolute methanol at about roomtemperature produces N-acetyl-4-hydroxyoctahydroindole, while is thentaken up in benzene or methylene chloride, and oxidized with an aqueoussolution of sodium dichromate acidified with acetic acid and sulfuricacid, as more particularly set forth in Preparation 13, at a temperatureof between about five and ten degrees centigrade to formN-acetyl-4-ketooctahydroindole.

PREPARATION 2 By treatment with dilute alkaliN-acetyl-4-ketooctahydroindole is hydrolyzed to 4-ketooctahydroindole.

PREPARATION 3 Following the procedure of Preparation 1, 7-methoxyindole(Blaikie and Perkin, 10c. cit.) is similarly convert ed toN-acetyl-7-ketooctahydroindole which can be hydrolyzed as in Preparation2 to 7-ketooctahydroindole.

PREPARATION 4 Reacting the compound of Preparation 2 and thecorresponding 7-ketooctahydroindole with an alkyl halide, e.g., methyliodide, ethyl bromide, isopropyl bromide, octyl bromide, or with asubstituted alkyl halide, e.g., ethyl bromoacetate,fl-bromoacetonitrile, methyl fl-bromopropionate, etc., produces thecorresponding N-substituted ketooctahydroindoles. These compounds arealso obtained by substituting the acetic anhydride of Preparations 1 and3 by the above halides.

PREPARATION 5 Reacting o-hydroxyphthalic anhydride [Bentley, Robinsonand Weizmann, J. Chem. Soc. 91, 111 (1907)] with ammonia produceso-hydroxyphthalimide which is converted, by reduction with lithiumaluminum hydride, to 4-hydroxyisoindoline which is then hydrogenated bythe procedure of Preparation 1 to form 4-hydroxyoctahydroisoindole. Thiscompound if then oxidized by the Oppenauer method to4-ketooctahydroisoindole.

By substituting the ammonia by primary amines such as methylamine,ethylamine, isobutylamine, 2-ethy1hexylamine, and like lower-alkylamines, benzylamine, cyclohexylamine, aniline, Z-aminopyridine,2-furylamine, furfurylamine, ethanolamine, and the like,4-ketooctahydroisoindoles N-substituted by the corresponding unchanged,or hydrogenated, and/or oxidized radicals are obtained.

4-ketooctahydroisoindole can also be acylated with acetic anhydride, orthe like, either before or after the oxidation. In the former case, thechromic acid oxidation of Preparation 1 can be used instead of theOppenauer method.

PREPARATION 6 Hydrogenating 4-hydroxybenzofuran [Reichstein and Hirt,Helv. Chim. Acta 16, 121 (1933)] with hydrogen in the presence ofpalladium on asbestos at about degrees centigrade (or Raney nickel inthe presence of a trace of alkali as in Preparation 1) produces4-hydroxy-. octahydrobenzofuran which is converted, upon oxidation bythe procedure of Preparation 1, to 4-ketooctahydrobenzofuran.

PREPARA'rrON 7 Substituting 7-hydroxybenzofuran obtained bydecarboxylating 2-carboxy-7-hydroxybenzofuran [Reichstein and Griissner,Helv. Chim. Acta 16, 555 (1933)] for the 4-hydroxybenzofuran in thereactions described in Prep aration 6 above produces7-ketooctahydrobenzofuran.

PREPARATION 8 CH: CH:

Reacting the o-hydroxyphthalimide described in Preparation 5 with amixture of zinc and copper in the presence of sodium hydroxide produces,along with the other isomer, the disodium salt of3-hydroxy-2-hydroxymethylbenzoic acid which, upon acidification withhydrochloric acid, is converted to 4-hydroxyisobenzofuran-3-one. 4-hydroxyisobenzofuran-3-0ne is reacted with methyl magnesium bromide toproduce 1,1-dimethyl-4-hydroxyisobenzofuran [see Ludwig, Ber. 40, 3060(1907)] which is converted, upon hydrogenation with hydrogen in thepresence of platinum, to 1,l-dimethyl-4-hydroxyoctahydroisobenzofuran.Oxidation of l,l-dimethyl-4-hydroxyoctahydroisobenzofuran with chromicacid in the manner described in Preparation 1, produces1,1-dimethyl-4-ketooctahydroisobenzofuran.

Similarly, the disodium salt of 2-hydroxy-6-hydroxymethylbenzoic acid isconverted by the same reactions to1,1-dimethyl-7-ketooctahydroisobenzofuran.

PREPARATION 9 PREPARATION 10 Substituting7-keto-4,5,6,7-tetrahydrothionaphthene as starting material in thereactions described in Preparation 9 above produces7-ketooctahydrothionaphthene and the corresponding sulfoxide andsulfone.

PREPARATION 11 Substituting 4-keto-4,5,6,7-tetrahydroisothionaphthene[Steinkopf et al., Ann. 536, 128 (1938)] in the reactions described inPreparation 9 above produces 4-ketooctahydroisothionaphthene and thecorresponding sulfoxide and sulfone.

PREPARATION 12 hydrothionaphthene, which is then oxidized by theOppenauer oxidation to 4-methoxy-7-ketooctahydrothionaphthene.

The sulfoxide and sulfone are prepared as in Preparation 9.

PREPARATION 13 A solution of 16.7 grams of S-hydroxyisoquinoline in 200milliliters of glacial acetic acid was hydrogenated at three atmospherespressure in the presence of one gram of Adams catalyst. When thetheoretical two molar equivalents of hydrogen had been taken up, thehydrogenation was stopped, the catalyst removed, and the solventdistilled at reduced pressure. The residue ofhydroxy-l,2,3,4-tetrahydroisoquinoline was dissolved in 140 millilitersof hot methanol and 25 milliliters of acetic anhydride was added insmall portions. After heating for one-half hour, the solvent wasdistilled at reduced pressure and the residue dissolved in the dilutesodium hydroxide, stirred with decolorizing charcoal, filtered, and theN-acetyl-S-hydroxy-l,2,3,4-tetrahydroisoquinoline was precipitated withhydrochloric acid. The precipitated product, after drying, weighed 18.3grams and melted at 172 to 174 degrees centigrade.

A mixture of 95.5 grams of N-acetyl-S-hydroxy-1,2,3,4-tetrahydroisoquinoline, produced according to the above procedure, threesodium hydroxide pellets, about fifteen to twenty grams of Raney nickelcatalyst, and 350 milliliters of absolute ethanol was shaken at 120degrees centigrade at an initial hydrogen pressure of 1600 pounds persquare inch at room temperature. When the theoretical three moles ofhydrogen had been absorbed, the hydrogen was removed, the catalystfiltered off and the solvent distilled, leaving a residue of 82 grams ofN-acetyl-S-hydroxy-decahydroisoquinoline boiling at 163 to 166 degreescentigrade at between 0.20 and 0.25 millimeter of mercury pressure.

To the above 82 grams of N-acetyl-S-hydroxydecahydroisoquinolinedissolved in 430 milliliters of thiophenefree benzene was added dropwiseat six to eight degrees centigrade a solution of 43.5 grams of sodiumdichromate dihydrate in sixty milliliters of concentrated sulfuric acid,185 milliliters of water, and 34 milliliters of glacial acetic acid. Theaddition took one hour. Stirring and cooling were continued for 75minutes thereafter, after which the mixture was permitted to warm toroom temperature. The reaction mixture was neutralized with aqueousammonia and the reaction product extracted with diethyl ether. The etherlayer was separated and the aqueous layer extracted several times withether which was added to the separated ether layer. The combined etherextracts were washed successively with an aqueous sodium bicarbonatesolution, an aqueous sodium chloride solution, and finally dried withanhydrous sodium sulfate. The ether was distilled leaving a residue ofsixty grams of N- acetyl-S-ketodecahydroisoquinoline, distilling at 154to 157 degrees centigrade at 0.7 millimeter of mercury pressure. I

PREPARATION 14 C") (IJOCHa A mixture of 200 grams of 8-hydroxyquinoline,five sodium hydroxide pellets, and about 250 milliliters of absoluteethanol was hydrogenated in the presence of Raney nickel catalyst at aninitial pressure of 2000 pounds per square inch at room temperature. Thetemperature was gradually raised to sixty degrees centigrade wherehydrogenation commenced and to degrees where it was complete after fourhours. The temperature was raised to degrees centigrade to ensurecomplete hydrogenation but no further uptake of hydrogen occurred. Afterremoval of catalyst by filtration, the solution was distilled, giving175 grams of 8-hydroxydecahydroquino line boiling at 104 degreescentigrade at one millimeter of mercurypressure. This compound, a clearviscous oil, gradually crystallized on standing.

Following the acetylation and oxidation procedures described inPreparation 13, two fifty-gram portions of the thus-produced8-hydroxydecahydroquinoline were separately converted to about 43 gramseach of crude N-acetyl- 8-hydroxydecahydroquinoline which was oxidizedwithout purification to N-acetyl-S-ketodecahydroquinoline. The combinedyield of N-acetyl-8-ketodecahydroquinoline, distilling at to 161 degreescentigrade at a pressure of between 0.4 and one millimeter of mercury,was- 34 grams. The ketone is a thick oil exhibiting a strong carbonylband at 5 .79 microns and a stronger amide band at 6.16 microns.

Similarly, S-hydroxyquinoline is converted to N-acetyl-S-ketodecahydroquinoline and 8-hydroxyisoquinoline is converted toN-acetyl-8-ketodecahydroisoquinoiine.

By hydrolyzing the N-acetyl group with dilute aqueous alkali or acid,there are obtained 8-ketodecahydroquinoline, 5-ketodecahydroquinoline,and 8-ketodecahydroiso-- quinoline, which can be alkylated if desired bythe procedure of Preparation 4.

Treatment of the above 8-hydroxydecahydroquinoline with an alkyl halide,e.g., methyl iodide, ethyl bromide, allyl chloride, benzyl chloride,octyl bromide, etc., produces the correspondingN-substituted-S-hydroxydecahydroquinoline, which can then be oxidized tothe N-substituted-8-ketodecahydroquinoline.

PRnPAnAnoN 15 Hydrogenation of S-hydroxyquinoline with hydrogen in thepresence of platinum oxide produces 8-hydroxy-l,2,3,4-tetrahydroquinoline. Trea ment of this compound with benzoyl chlorideproduces the N-benzoyl derivative which is converted with phosphorouspentachloride to 2-hydroxy-6('y-chloropropyl)-benz,anilide.Saponification of the N-benzoyl group and diazotization of thethus-produced free amino group produces 3-('y-chloropropyl)-catecholwhich is cyclized with sodium hydroxide to 3,4-dihydro-S-hydroxy-l,2-benzopyran. This compound is then hydrogenated andoxidized by the procedure of Preparation 1 to8-ketooctahydro-1,2-benzopyran. Similarly, S-hydroxyquinoline isconverted to S-ketooctahydro-1,2-benzopyran.

PREPARATION 16 A mixture of eighteen grams of 2-hydroxymethylene-1-decalone [Johnson and Posvic, I. AmpChem. Soc. 69, 1361 (1947)], 40.5grams of ethylene-bis-p-toluenethim sulfonate (prepared by the reactionof ethylene bromide and potassium'p-tolylthiosulfonate according to theprocedure of Chivers and Smiles, J. Chem. Soc. 1928, 697),. sixty gramsof potassium acetate, and 650 milliliters ofabsolute ethanol wasrefluxed for six hours in a nitrogen atmosphere. The solvent was thenremoved at reduced pressure with heating on a steam bath. The residuewas dissolved in a mixture of diethyl ether and water. A small quantityof crystals melting at 201 to 204 degrees centigrade was filtered off.The ether solution was separated, washed successively with a fivepercent aqueous solution of sodium hydroxide, then with water until thewashes were neutral, then with saturated aqueous sodium chloride, andfinally dried with anhydrous magnesium sulfate. The ether was distilled,and the residue was recrystallized from methanol to give eleven grams ofthe 2-ethylene glycol dithioketal of 1,2-diketodecahydronaphthalenemelting at 96 to 97 degrees centigrade as the first crop and 3.5 gramsas the second crop.

Analysis.Calculated for C H OS C, 59.50; H, 7.48. Found: C, 59.48; H,7.27.

PREPARATION 17 Hydrogenation of7-methyl-9-methoxy-1,2,3,4-tetrahydrophenanthren-l-one [Ruzicka andWaldmann, Helv. Chim. Acta 15, 907-14 (1932)] with Raney nickel catalystproduces l-hydroxy 7 methyl-9-methoxytetradecahydrophenanthrene which,when oxidized with chromic acid, produces7-methyl-9-methoxytetradecahydrophenanthren-l-one.

PREPARArIoN 18 Diazotization of 4-amino-l-hydrindenone (Ingold, J. Chem.Soc. 123, 1469) followed by reaction with hydrochloric acid produces4-hydroxy-l-hydrindenone. Ketalization of 4-hydroxy-l-hydrindenone withethylene glycol in the presence of p-toluenesulfonic acid produces thecorresponding l-ethylene glycol ketal. Hydrogenation of the l-ethyleneglycol ketal of 4-hydroxy-1-hydrindenone with hydrogen in the presenceof Raney nickel catalyst at high pressure produces the l-ethylene glycolketal of 4- hydroxy-l-hydrindanone. Oxidation of the l-ethylene glycolketal of 4-hydroxy-l-hydrindanone with N-bromoacetamide in the presenceof pyridine produces hydrindane-l,4-dione-1-ethylene glycol ketal.

PREPARATION 19 o 8 II l COOCH;

Quaternization of S-hydroxyisoquinoline with methyl iodide followed byhydrogenation at low pressure with a platinum catalyst, producesS-hyroxy-N-methyl-1,2,3,4- tet-rahydroisoquinoline. Iodination of thislatter compound by the procedure of Haworth and Perkin, J. Chem. Soc.127, 1434 (1925) produces 5-hydroxy-3,4-dihydroisoquinoline methiodide,which when reacted with sodium cyanide, followed by hydrolysis withsulfuric acid, is converted toS-hydroxy-N-methyl-l-carboxy-1,2,3,4-tetrahydroisoquinoline. This lattercompound is then reduced witl hydrogen at high pressure in the presenceof Raney nickel catalyst toS-hydroxy-N-methyl-l-carboxydecahydroisoquinoline, which is thenoxidized with chromic acid toS-keto-N-methyl-1-carboxydecahydroisoquinoline.

Esterification of the carboxy group with di-azomethane followed bycondensation of the esterified compound with sodium methoxide and ethylformate produces 5-keto-6- formylN-methyl-l-carbomethoxydecahydroisoquinoline. This compound, whenreacted with ethylene-bis-p-toluenethiosulfonate in the presence ofsodium acetate, produces 5,6 diketo N methyl 1carbomethoxydecahydroisoquinoline-G-e'thylene glycol dithioketal.

PREPARATION 20 N-O OCH:

oon

Methylation of S-hydroxyisoquinoline produces 5- methoxyisoquinolinewhich is converted by the Reissert reaction tol-cyano-S-methoxyisoquinoline. Hydrolysis of this nitrile producesl-carboxy-S-methoxyisoquinoline. Demethylation of the latter by etherhydrolysis produces 1-carboxy-5-hydroxyisoquinoline. Hydrogenation ofthis latter compound at low pressure with platinum catalyst followed byacetylation of the hydrogenation product with acetic anhydride, producesS-hydroxy-l-carboxy-N-acetyl- 1,2,3,4-tetrahydroisoquinoline. Raneynickel catalyzed high pressure hydrogenation of this compound produces 5hydroxy 1 carboxy-N-acetyldecahydroiscrquinoline which is converted,upon oxidation with chromic acid, to5-keto-1-carboxy-N-acetyldecahydroisoquinoline.

PREPARATIoN 21 CHaOOC Hydrogenation of ethyl a-resorcylate with one moleof hydrogen in the presence of Raney nickel catalyst and sodiumhydroxide produces S-carbethoxy-cyclohexane-1,3- dione. Condensation ofvinylamine with S-carbethoxycyclohexane 1,3 dione produces 2 (2aminoethy1)-5- carbethoxy-cyclohexane-l,S-dione which immediatelycyclizes and is converted, upon hydrogenation with one mole of hydrogenat low pressure in the presence of a platinum catalyst, to4-keto-6-carbethoxyoctahydroindole.

PREPARATION 22 S-m-methoxybenzylthioglycolic acid is cyclized byFriedel-Crafts ring closure using hydrogen fluoride or otherFriedel-Crafts catalyst [Ben 56, 1642 (1923); Ber. 62, 2416 (1929)] toform 4-keto-5-methoxyisothiochroman. With or without the separation ofthe 7-methoxy isomer, S-methoxyisothiochroman is obtained by a Wolff-Kishner reduction with hydrazine. On hydrolysis with acid or aluminumchloride followed by hydrogenation with a large excess of platinum,S-hydroxyhexahydroisothiochroman is obtained. This compound is thenconverted to S-ketohexahydroisothioehroman by an Oppenauer oxidation.

The S-m-methoxybenzylthioglycolic acid is prepared by reactingm-methoxybenzyl bromide [Woodward, I. Am. Chem. Soc. 62, 1481 (1940)]with methyl thioglycolate in potassium hydroxide solution followed byacid hydrolysis of the resulting ester.

PREPARATION 23 -keto2,3,4,5-tetrahydro l benzoxapin [Powell andAnderson, J. Am. Chem. Soc. 53, 811 (1931)] is nitrated with a mixtureof nitric and sulfuric acid and then hydrogenated with a palladiumcatalyst to 9-amino-5-hydroxy-2,3,4,5-tetrahydro-l-benzoxapin which ontreatment with nitrous acid and sulfuric acid (diazotization) isconverted to 5,9-dihydroxy-2,3,4,5-tetrahydro-l-benzoxapin. Thiscompound is then hydrogenated with palladium on charcoal at about 65degrees centigrade and then with platinum in acetic acid (or with Raneynickel and a trace of alkali as in Preparation 1) to9-hydroxydecahydro-l-benzoxapin which is then oxidized by the procedureof Preparation 1 to 9-ketodecahydro-l-benzoxapin.

PREPARATION 24 S-keto-l,2,4,5-tetrahydro-3-benzothiepin [V. Braun andWeissbach, Ber. 62, 2416 (1929)] is reduced by the Woltf-Kishnerprocedure and then sulfonated to produce9-sulfo-1,2,4,5-tctrahydro-3-benzothiepin which in turn is converted tothe corresponding 9-hydroxy compound by alkali fusion. The resulting9-hydroxy-1,2,4,5-tetrahydro-3-benzothiepin is hydrogenated with atleast two equivalents of platinum and then oxidized with aluminumisopropoxide in acetone to the desired 6-ketodecahydro- 3-benzothiepin.

The sulfoxide and sulfone are prepared by further oxidation withhydrogen peroxide by the usual procedure.

sulfoxide and sulfone are prepared by the procedure of Preparation 24from 1,4,5,Qa-tetrahydro-2-benzothiepin [V. Braun, Ber. 58, 2165(1925)].

PREPARATION 26 2,3,4,5-tetrahydro-l-benzazepine [V. Braun, Ber. 40, 1834(1907)] is acetylated with acetic anhydride and nitrated with a mixtureof nitric and sulfuric acids to produceN-acetyl-9-nitro-2,3,4,5-tetrahydro-l-benzazepine in admixture withother isomers. With or without separation, theN-acetyl-9-nitro-2,3,4,5-tetrahydro-l-benzazepine is hydrogenated withplatinum on charcoal and the resulting amine diazotized to the 9-hydroxycompound. The resulting N-acetyl-9-hydroxy-2,3,4,S-tetrahydro-1-benzazepine is then perhydrogenated with platinum in acetic acid (orwith Raney nickel and a trace of alkali as in Preparation 1), and thenoxidized by the procedure 35 of Preparation 1 toN-acetyl-9-ketodecahydro-l-benzazepine.

if desired, the N-acetyl group can now be hydrolyzed to give9-ketodecahydro-1-benzazepine, which in turn can be alkylated as inPreparation 4.

PREPARATION 27 0 CH1 0 O I! j H Boos-0H N-H PREPARATION 28 4,6-diketoa,5,9a-trimethyldecahydro-3 benzazepine- 7-acetic acid (Preparation 27)is reduced with lithium aluminum hydride to6-hydroxy-5,9a-dimethyl-7-(p-hydroxyisopropyl)-decahydro-3-benzazepinewhich, after acetylatlon to protect the nitrogen, is reoxidized withchromic acid by the procedure of Preparation 1 to form3-acetyl-6-keto-a,5,9a trimethyldecahydro-Ii-benzazepine- 7-acetic acid.The 3-acetyl group can then be hydrolyzedmethyldecahydro-3-benzazepine-7-acetic acid.

The same compound is also obtained by reducing the starting compound ofPreparation 27 with lithium aluminum hydride first and thenhydrogenating with palladium on charcoal, followed by the chromic acidoxidation.

by acid or alkaline hydrolysis to give 6-keto-a,5,9a-tri- PREPARATION 29CHzO l-keto-8-methoxy 1,2,3,4,11,12 hexahydrochrysene [Chuang, Ber. 70,858 (1937)] is hydrogenated with ten percent palladium charcoal to give1-keto-8-methoxy-1,2, 3,4,4a,1 1,12,12a-octahydrochrysene.

PREPARATION 30 9-ketO-1,2,3,9,10,10a-hexahydropyrene [Bachmann andEdgerton, J. Am. Chem, Soc. 62, 2970 1940)] is bydrogenated with Raneynickel plus a trace of alkali, and then oxidized with chromic acid, bothby the procedures of Preparation 1, to give 9-ketohexadecahydropyrene.

PREPARATION 31 By the procedure of Preparation 30,4-ketooctadecahydrobenzo[c]phenanthrene is obtained from 4-keto-1,2,3,4-tetrahydr'obenzo[c]phenanthrene (Bachmann and Edgerton, loc. cit.).

PREPARATION 32- the By the procedure of Preparation 32,1,3-diketodecahydronaphthalene-3-ethylene glycol ketal is obtained from1,3-diketodecahydronaphthalene [Ruzicka, Helv. Chim. Acta 14, 1151(1931)].

-- PREPARATION 34 l-amino-S-cyanonaphthalene [Cason, 'I. Am. Chem.

PREPARATION 35 1-hydroxy-4-carbomethoxydecahydronaphthalene [Arnold, J.Am. Chem. Soc. 66, 208 (1944)] is oxidized with chromic acid by theprocedure of Preparation 1 to give 4-carbomethoxy-1-decalone.

PREPARATION 36 By acid hydrolysis of the acetyl group of l-acetamido-4-nitro-5-carboxynaphthalene [Ekstrand, I. Prakt. Chem. [27] 38, 244(1888)] and diazotization of the resulting amino group, there isobtained 1-hydroxy-4-nitro-5-carboxynaphthalene which, afteresten'fication with diazomethane, is hydrogenated with Raney nickel plus-a trace of alkali by the procedure given in Preparation 1 to 4-amino-S-carbomethoxy-l-decalol. This compound is then acylated withacetic anhydride to protect the amino group and then oxidized withchromic acid by the procedure in Preparation 1 to give4-acetamido-4-carbome'thoxy-1- decalone.

A concomitant product is the corresponding lactam which may be separatedby means of an acid wash or vacuum distillation.

By means of alkali or acid hydrolysis, the 4-acetamido-S-carbomethoxyd-decalone is converted to 4-amino-5- carboxy-l-decalone.

PREPARATION 37 i PREPARATION 38 By the procedure of Preparation 30,6-carboxy-1- naphthol (Butler and Royal, J. Chem. Soc. 123, 1653-4) isconverted to G-carboxy-l-decalone and 6-carbomethoxyl-naphthol to6-carbomethoxy-l-decalone.

PREPARATION 39 The lactone of 1-nitro4-hydroxy-5-carboxynaphthalene(Ekstrand, loc. cit.) is hydrogenated with a platinum catalyst and thel-amino group thus formed diazotized to form the corresponding lactonewhich, on hydrogenation and oxidation by the procedure of Preparation 1,is converted to the lactone of 4-hydroxy-5carboxy-l-decalone.

(exec-t in the case of a blocked keton PREPARATION 40 PREPARATION 41 Bythe procedure of Preparation 30, l-hydroxy-S- carboxy-naphthalene(Cassilla and Co. D.R.P. 459,404; Frdl. 15, 1809) is converted to8-carboxy-1-decalone.

When the ketone contains a basic nitrogen groumn the D-ring, as inPreparations 2, 3, 4 5, 14, 19, 21, 26, 28, and 37, or when amido groupsas in Preparations 13 and 20 are hydrolyzed to yield a basic nitrogengroup, the amino ketones can be reacted with fiuosilicie acid to formamine fiuosilicates useful for mothproofing in accordance with US.Patents 1,915,334 and 2,075,359; or they can be reacted with thiocyanicacid to form the thiocyanate salt and this in turn reacted withformaldehyde according to US. Patents 2,425,320 and 2,606,155

to form iclilin inhibitors.

.The intermeiiate Hydrazones obtained according to thgnvention fromlfetoneshavmg a basic nitrogen gropp in the D-ring similarly can bereacted with fiuosilicic acid to form mothproofing agents, or with thiocan'c acid and formaldehyde to form picklin inhibitors.

fxlscfihe isomeric hydrocarbazoles which are formed 1 O I I I a j Itained from ketones having a basic nitrogen grgup in the D-ring, canalso be reacted with tluosilicic acid to form amine fiuosilicates usefulas mothproofing agents having the advantage of high molecular weight,and with thiocyanic acid and formaldehyde to form pickling inhibitors.

"The following examples are illustrative of hydrocarbazolenines of thepresent invention, and procedures for their preparation, but are not tobe construed as limiting.

Example I .-1,2,3,4,4a,5,6,7-ctahydr0benz [d] Jail-isocarbazole Amixture of 30.4 grams of trans-l-decalone and 21.6 grams ofphenylhydrazine was heated slightly above room temperature for about tenminutes in the presence of a few drops of acetic acid. To thethus-produced phenylhydrazone of a-decalone was added 350 milliliters ofglacial acetic acid and the solution was refluxed for about two hoursunder nitrogen. The glacial acetic acid was distilled at reducedpressure and the residue was mixed with ether and aqueous sodiumhydroxide. The ether solution was washed with dilute hydrochloric acid.From the ether layer was isolated about three grams of l-decalone, and7.3 grams of a thick oil which distilled when heated in an oil bath at175 to 210 degrees centigrade at 0.6 millimeter of mercury pressure andconsisted of 1,2,3,4,4a,5,6,l1b octahydro 11 benzo[a]carbazole. Thedesired hydrocarbazolenine, which is isomeric with the abovehydrocarbazole, was isolated from the aqueous acid phase as follows:

The dilute hydrochloric acid wash was made alkaline and extracted withether. The ether solution was dried, the ether was removed bydistillation, and the residue was vacuum distilled to yield thirty gramsof oily 1,2,3,4, 4a,5,6,7-octahydrobenz[d] 4aH isocarbazole boiling at160 to 170 degrees centigrade at 0.4 millimeter of mercury pressure. Thehydrocarbazolenine, which crystallized on standing, was recrystallizedfrom cyclohexane and melted at 74 to 75.5 degrees centigrade.

Analysis.Calculated for C H N: C, 85.3; H, 8.49. Found: C, 85.3; H,8.56.

The picrate (yellow) melted at 189.5 to 191.5 degrees centigrade.

Analysis-Calculated for 0,,H,,N,0,= C, 58.2; H, 4.89. Found: C, 58.5; H,5.18.

The hydrochloride, prepared by passing gaseous hydrogen chloride into anacetone solution of the hydrocarbazolenine, melted at 225 degreescentigrade with decomposition when placed in a melting bath at 210degrees centigrade.

Analysis.Calculated for C H ClN: C, 73.6; H, 7.70. Found: C, 73.86; H,7.75.

The methiodide, prepared by adding methyl iodide to an ethyl acetatesolution of the hydrocarbazolenine, melted at 224 to 225.5 degreescentigrade.

By substituting cis-l-decalone for the above trans-ldecalone, there isobtained 1,2,3,4,4a,5,6,7-octahydrobenz[d]-4aH-isocarbazole identicalwith that described above.

Example 2.-1 ,2,3,4,4a,5 ,6, 7-octahydrobenz [d 4aH-isocarbazoIe Amixture of ten grams of trans-l-decalone, seven grams ofphenylhydrazine, and five drops of acetic acid was heated for about tenminutes on a steam bath. To the resulting phenylhydrazone of a-decalonewere added 250 milliliters of absolute ethanol and twenty milliliters ofconcentrated sulfuric acid, and the solution was heated at refluxtemperature for two hours. A solution consisting of thirty grams ofsodium hydroxide and 75 milliliters of water was added, and the solventwas removed in vacuo on a steam bath. The resulting residue was thenworked up as described in Example 1 to obtain 2.5 grams of1,2,3,4,4a,5,6,7 octahydrobenz[d] 4aH isocarbazole and twelve grams ofthe isomeric hydrocarbazole.

Example 3.-9-methoxy-1,2,3,4,4a,5,6,7-

octahydrobenz [d] -4aH-isocarbazole CHIO Following the proceduredescribed in Example 1, twenty grams of o-methoxyphenylhydrazine wasreacted with 22 grams of trans-l-decalone to produce theo-methoxyphenylhydrazone of trans-l-decalone. The latter was cyclized inthe same manner as described in Example 1 to produce a mixture whichwhen worked up as described in Example 1 yielded 3.4 grams of unreacted1- decalone, 10.4 grams of the isomeric hydrocarbazole, and fourteengrams of 9-methoxy-1,2,3,4,4a,5,6,7-octahydrobenz[d]-4aH-isocarbazolewhich distilled when heated in an oil bath at to degrees centigrade, ata pressure of 0.1 to 0.2 millimeter of mercury. The hydrocarbazolenine,after recrystallization from a mixture of cyclohexane and petroleumether, melted at 77 to 78 degrees centigrade.

Analysis-Calculated for C H N0: C, 80.0; H, 8.31. Found: C, 79.86; H,8.25.

The picrate (yellow) melted with decomposition at 191 to 193 degreescentigrade.

Analysis.Calc. for C23H24N403: C, H, N, 11.57. Found: C, 56.9; H, 4.92;N, 10.95, 12.03.

A crystalline methiodide was also obtained.

Example 4.3-acetyl-1,2,3,4,4a,5,6,7-octahydropyrid- [3,4 -d-4aH-isocarbazole COCH:

To ten grams of N-acetyl-S-ketodecahydroisoquinoline was added 5.6 gramsof freshly distilled phenylhydrazine. There was an immediate evolutionof heat. Fifteen milliliters of glacial acetic acid was added and afterfive minutes, the solution was cooled and the flask scratched to producecrystallization. The crystals were separated by' centrifuging themixture and were washed with a little glacial acetic acid followed byanhydrous ethanol. There was thus obtained 13.1 grams of thephenylhydrazone of N-acetyl-S-ketodecahydroisoquinoline melting withdecomposition at 225 to 234 degrees centigrade. After two digestionswith anhydrous ethanol, the product weighed 12.7 grams and melted withdecomposition at 236 to 238 degrees centigrade.

Analysis-Cale. for C17H23N3OI C, 71.6; H, 8.13; N, 14.72. Found: C,72.04; H, 8.18; N, 14.41.

Following the procedure described in Example 1, a mixture consisting ofthe phenylhydrazone of N-acetyl-S-ketodecahydroisoquinoline dissolved inglacial acetic acid was heated at reflux temperature for about twohours. The thus-produced 3-acetyl-1,2,3,4,4a,5,6,7 octahydropyrid-'[3,4-d]-4aHisocarbazole was freed of solvent by distillation at reducedpressure and isolated by the work-up procedure described in Example 1;the compound distilled at an oil bath temperature of 210 to 225 degreescentigrade at a pressure of 0.3 to 0.5 millimeter of mercury. Some ofthe isomeric hydrocarbazole was also produced in the reaction and wasobtained from the ether wash.

The picrate (yellow) of 3-acetyl-9-methoxy-1,2,3,4,4a,5,6,7-octahydropyrid[3,4-d]-4aH-isocarbazole was prepared.

Analysis.-Calc. for C23H23N503I C, 55.6; H, N, 14.09. Found: C, 55.6; H,4.90; N, 14.0.

The picrate of the isomeric hydrocarbazole was also prepared. It has adark, reddish brown color. Generally speaking, the picrates of thehydrocarbazolenines of the invention are yellow, while the picrates ofthe isomeric, concomitantly-produced hydrocarbazoles are dull red orbrown.

The 3 acetyl-1,2,3,4,4a,5,6,7 octahydropyrid[3,4-d]- 4aH-isocarbazolecan be deacetylated by heating in dilute aqueous sodium hydroxide. The1,2,3,4,4a,5,6,7-octahydropyrid[3,4-d]-4aH-isocarbazole thus obtainedcan, if desired, be alkylated by the procedure of Preparation 4 to givethe corresponding N-substituted-l,2,3,4,4a,5,6,7-octahydropyrid[3,4-d]-4aH-isocarbazole.

Example 5 .--3-acetyl-9-methoxy-I ,2,3,4,4a,5 ,6,7 -0ctahydropyrid[3,4-d] -4aH-isocarbazole 00GB: l

e In the same manner as described in Example 4 theo-methoxyphenylhydrazone of N-acetyl-S-ketodecahydroisoquinoline wasconverted to 3-acetyl-9-methoxy-1,2,3,4,4a,5,6,7-octahydropyrid[3,4-d]-4aH-isocarbazole.

Example 6.-1-acetyl-1,2,3,4,4a,5,6,7-octahydropyrid [3,2-d]-4aH-isocarbaz0le Following the procedure described in Example 1. tengrams of N-acetyl-8-ketodecahydroquinoline and 5.5 grams ofphenylhydrazine were converted to the phenylhydrazone ofN-acetyl-8-ketodecahydroquinoline, which was then cyclized in glacialacetic acid to produce 1- aeetyl 1,2,3,4,4a,5,6,7octahydropyrid[3,2-d]-4aH-isocarbazole which distilled, at a pressure of0.5 to 1.0 millimeter of mercury, when heated in an oil bath at 155 to180 degrees centigrade.

fixample 7 .-7-ke t o-'I ,2,3,4,4a,5,6,7-octahydr0benz [d]-4aH-isocarbazole 7-ethylene glycol dithioketal Following the proceduredescribed in Example 1, six grams of the 2-ethylene glycol dithioketalof 1,2-diketodecahydronaphthalene and 2.7grams of phenylhydrazine wereheated on a steam bath with four drops of acetic acid for fifteenminutes. There was then added an additional milliliters of glacialacetic acid and the mixture was refluxed for two hours. The work-upprocedure of Example 1 yielded 4.3 grams of starting ketone, and 0.8gram of 7-keto-1,2,3,4,4a,5,6,7-octahydrobenz[d]- 4aH-isocarbazole7-ethylene glycol dithioketal melting without recrystallization at 153to 155 degrees centigrade, and at 155 to 155.8 degrees centigrade afterrecrystallization from ethanol, and soluble in moderately stronghydrochloric acid.

Analysis.-Calculated for CmHmNSgi C, 68.5; H, 6.72. Found: C, 68.6; H,6.86.

The yellow picrate, after recrystallization from ethanol, meled withdecomposition at 163 to 164 degrees centigra e.

Analysis.Calc. for C H N O S C, 53.0; H, 4.45. Found: C, 53.04; H, 4.52.

Example 8.7-ket0-9-meth0xy-1,2,3,4,4a,5,6,7-0ctahydrobenz-[d1-4aH-isocarbaz0le 7-ethylene glycol dithioketal 0H. s s

Following the procedure described in Example 1, 4.7 grams of the2-ethylene glycol dithioketal of 1,2-diketodecahydronaphthalene ando-methoxyphenylhydrazine were converted to7-keto-9-methoxy-1,2,3,4,4a,5,6,7-octahydrobenz[d]-4aH-isocarbazole7-ethylene glycol dithio- 31 ketal melting, after recrystallization fromaqueous ethanol, at 176 to 177 degrees centigrade.

Analysis.Calculated for C H NOS C, 66.1; H, 6.72. Found: C, 65.9; H,6.57.

The yellow picrate, after recrystallization from ethanol, melted withdecomposition at 176 to 177 degrees centigrade also.

Analysis.--Calc. for C H N O S C, 52.3; H, 4.56. Found: C, 51.83; H,4.75.

Any Z-hydroarylhydrazine, as exemplified above, and any fusedhydroaromatic ketone having a vicinal bridgehead-hydrogen atom, asexemplified above, can be substituted in the procedures set forth in theforegoing examples to form arylhydrazones which can be cyclized to thecorresponding hydrocarbazolenines by the procedures also set forth inthe foregoing examples. The following examples illustrate representativehydrocarbazolenines which can thus be obtained.

Example 9 The p-nitrophenylhydrazone of l-decalone is prepared andcyclized by the procedure of Example 1 to give the abovehydrocarbazolenine.

Example 10 The p-bromophenylhydrazone of 4-hydrindanone is prepared andcyclized by the procedure of Example 1 to give the abovehydrocarbazolenine.

Example 11 cyclized by the procedure of Example 1 to give the abovehydrocarbazolenine.

Example 12 The fi-naphthylhydrazone of 4-hydrindanone is prepared andcyclized by the procedure of Example 1 to give the abovebydrocarbazolenine.

32 Example 13 OOH The o-carboxyphenylhydrazone of7-ketooctahydrothionaphthene is prepared and cyclized by the procedureof Example 1 to give the above hydrocarbazolenine.

Example 14 CHaC O CH:CH1 l N OaN Example 15 HzN Thep-aminophenylhydrazone of N-acetyl-S-ketodecahydroisoquinoline isprepared and cyclized by the procedure of Example 1 to give the abovehydrocarbazolenine.

Example 16 OzN C O O CH:

The 2-carbomethoxy-4-nitrophenylhydrazone of 1- decalone is prepared andcyclized by the procedure of Example 1 to give the abovehydrocarbazolenine.

Example 17 The p-cyanophenylhydrazone of S-ketohexahydroisochroman isprepared and cyclized by the procedure of Example 1 to give the abovehydrocarbazolenine.

Example 18 The p-hydroxyphenylhydrazone of 3-isopropenyl-5,10- Example24 dimethyl-l-decalone is prepared and cyclized by the procedure ofExample 1 to ive the above hydrocarbazolenine.

Example 19 no I The phenylhydrazone of 4-carboxy-1-decalone is preparedand cyclized by the procedure of Example 1 to give the abovehydrocarbazolenine. CH Example 25 The phenylhydrazone of3,l2-dihydroxy-7-ketocholanic H000 acid is prepared and cyclized by theprocedure of Ex- 5 ample 1 to give the above hydrocarbazolenine. KExample 20 The phenylhydrazone of 7-carboxy-IO-methyl-l-decalone isprepared and cyclized by the procedure of Example 1 to give the abovehydrocarbazolenine.

Example 26 N The phenylhydrazone of 3-isopropyl-5,IO-dimethyl-ldecaloneis prepared and cyclized by the procedure of Example 1 to give the abovehydrocarbazolenine. 30

Example 21 I The phenylhydrazone of S-carboethoxy-l-decalone is preparedand cyclized by the procedure of Example 1 to give the abovehydrocarbazolenine. OCOOH: Example 27 The phenylhydrazone of4-acetoxy-1-decalone is pre- 40 pared and cyclized by the procedure ofExample 1 to give the above hydrocarbazolenine.

Example 22 AcO COOCH,

The phenylhydrazone of l-keto-2-methyl-2-carbo- 5omethoxy-7-methoxy-1,2,3,4,4a,9,10,10a-occohydrophenanthrene is preparedand cyclized by the procedure of Example 1 to give the abovehydrocarbazolenine. N/ Example 28 The phenylhydrazone offi-ketocholestanyl acetate is prepared and cyclized by the procedure ofExample 1 50 to give the above hydrocarbazolenine. Ae

The phenylhydrazone of 7-ketocholestanyl acetate is Example 23 preparedand cyclized by the procedure of Example 1 to give the abovehydrocarbazolenine. C1130 Example 29 OCH: 1:

The phenylhydrazone of 4,7-dimethoxy-l-decalone is prepared and cyclizedby the procedure of Example 1 to give the above hydrocarbazolenine.

The phenylhydrazone of 2,10-diphenyl-4-hydroxy-A Octalone is preparedand cyclized by the procedure of Example 1 to give the abovehydrocarbazolenine.

Example 30 The phenylhydrazone of 8-cyano-1-decalone is prepared andcyclized by the procedure of Example 1 to give the abovehydrocarbazolenine.

Example 31 The phenylhydrazone of 3 nitro-l-decalone is prepared andcyclized by the procedure of Example 1 to give the abovehydrocarbazolenine.

Example 32 The phenylhydrazone of 7-nitro-1-deca1one is prepared andcyclized by the procedure of Example 1 to give the abovehydrocarbazolenine.

Example 33 The phenylhydrazone of hydrinane-1,4-dione l-ethylene glycolketal is prepared and cyclized by the procedure of Example 1 to give theabove hydrocarbazolenine.

Example 34 ss II The p-tolylhydrazone of 1,Z-diketodecahydronaphthaleneZ-ethylene glycol thioketal is prepared and cyclized by the procedure ofExample 1 to give the above hydrocarbazolenine.

36 Example 35 CHaC 0- The phenylhydrazone of7-acetyl-lo-methyl-l-decalone is prepared and cyclized by the procedureof Example 1 to give the above hydrocarbazolenine.

Example 36 COOEt Example 37 .iAO N c0011 The p-chlorophenylhydrazone ofS-keto-l-carboxy-N- acetyldecahydroisoquinoline is prepared and cyclizedby the procedure of Example 4 to give the above hydrocarbazolenine.

The compound can be deacetylated, or deacetylated and then alkylated asin Example 4 if desired.

Example 38 COOCH:

The p-iodophenylhydrazone of the 6-ethylene glycol dithioketal of5,6-diketo-N-methyl-l-earbomethoxydecahydroisoquinoline is prepared andcyclized by the procedure of Example 4 to give the abovehydrocarbazolenme.

It is to be noted that in this example no hydrocarbazole is formedbecause of the blocking effect of the ethylene glycol dithioketal group.

37 Example 39 The o-nitrophenylhydrazone of7-rnethyl-9-methoxytetradecahydrophenanthren-l-one is prepared andcyclized by the procedure of Example 1 to give the abovehydrocarbazolenine.

Example 40 OzN NO \N/ N// The m-nitrophenylhydrazone ofS-ketooctahydrobenzopyran is prepared and cyclized by the procedure ofExample 1 to give a mixture of the above hydrocarbazolenines.

' Example 41 OzN The 2,4-dinitrophenylhydrazone ofN-acetyl-8-ketodecahydroquinoline is prepared and cyclized by theprocedure of Example 4 to give the above hydrocarbazolenine.

The compound can be deacetylated, or deacetylated and then alkylated asin Example 4 if desired.

Example 42 The m-tolylhydrazone of N-aeetyl-8-ketodecahydroisoquinolineis prepared and cyclized by the procedure of Example 4 to give a mixtureof the above hydrocarbazolenines.

These compounds can be deacetylated, or deacetylated and then alkylatedas in Example 4 if desired.

Example 43 The p-tolylhydrazone of N acetyl 5 ketodecahydro- 7 quinolineis prepared and cyclized by the procedure of Example 4 to give the abovehydrocarbazolenine.

Example 44 The bromo-o-tolylhydrazone of4-methoxy-7-ketooctahydrothionaphthene is prepared and cyclized by theprocedure of Example 1 to give the above hydrocarbazolemne.

The corresponding sulfoxide and sulfone are obtained by first oxidizingthe ketone with hydrogen peroxide to form the sulfoxide and sulfonethereof.

OCH:

Example 45 N Br The bromo p tolylhydrazone of7-ketooctahydroisothionaphthene is prepared and cyclized by theprocedure of Example 1 to give the above hydrocarbazolenine.

The corresponding sulfoxide and sulfone are obtained by first oxidizingthe ketone with hydrogen peroxide to form the sulfoxide and sulfonethereof.

Example 46 ('JHQ l Example 47 CH N// The 3,5 xylylhydrazone of 1,1dimethyl-7-ketooetahydroisobenzofuran is prepared and cyclized by theprocedure of Example 1 to give the above hydrocarbazolenine.

Example 48 CH! I The 2,4 xylylhydr-azone of 1,1 dimethyl-4-ketoocta- 39hydroisobenzofuran is prepared and cyclized by the procedure of Example1 to give the above hydrocarbazolerune.

Example 49 0011:, CHI! The phenyl-2,4 xylylhydrazone of 7ketooctahydrobenzofuran is prepared and cyclized by the procedure ofExample 1 to give the above hydrocarbazolenine.

Example 50 Q T OH, OzN

CH 1 N to,

The o-nitrobenzyl-m-tolylhydrazone of 4 ketooctahydrobenzofuran isprepared and cyclized by the procedure of Example 1 to give a mixture ofthe above hydrocarbazolenines.

Example 51 by the procedure of Example 1 to give a mixture of the abovehydrocarbazolenines.

Example 52 The 3-ethyl-2,4-dinitrophenylhydrazone of N-acetyl-4-ketooctahydroisoindole is prepared, cyclized, and deacetylated by theprocedure of Example 36 to give the above hydrocarbazolenine.

The N-hydrogen can be replaced, if desired, by alkylation by theprocedure set forth above.

Example 53 C2Ha The o-ethylphenylhydrazone of N-earbethoxymethyl-4-ketooctahydroindole is prepared and cyclized by the procedure of Example1 to give the above hydrocarbazolenine.

Example 54 CHsO 40 The 3,5 dichloro p anisylhydrazone of N acetyl-4-ketooctahydroindole is prepared, cyclized, and deacetylated by theprocedure of Example 36 to give the above hydrocarbazolenine.

The N-hydrogen can be replaced, if desired, by alkylation by theprocedure set forth above.

Example 55 The 4-bromo-l-naphthylhydrazone ofN-acetyl-7-ketooctahydroindole is prepared and cyclized by the proce--dure of Example 4 to give the above hydrocarbazolenine. The compound canbe deacetylated, or deacetylated and then alkylated as in Example 4 ifdesired.

Example 56 The m-anisylhydrazone of N-acety1-4-keto0ctahydroindole isprepared and cyclized by the procedure of Example 4 to give a mixture ofthe above hydrocarbazolenines.

The compounds can be deacetylated, or deacetylated and then alkylated asin Example 4 if desired.

Example 57 CH; (:11 CE: (EH:

The p-sec-butylphenylhydrazone of 3-ket0-7-methoxy- 1,2,3,9,10,11hexahydro 1,2 cyclopentenophenanthrene is prepared and cyclized by theprocedure of Example 1 to give the above hydrocarbazolenine.

Example 58 The S-chloro-2,4-dinitrophenylhydrazone of 6-keto- A-dodecahydrochrysene is prepared and cyclized by the procedure ofExample 1 to give the above hydrocarbazolenine.

1. A KETONE HAVING THE FORMULA: